Effects of a fluorinated bisphosphonate on bone remodeling in vivo

A new fluorinated bisphosphonate, difluoromethylene bisphosphonate (F2MBP), was studied for its effects on physiologic bone remodeling in the actively growing rat tibia. Young male Sprague-Dawley rats were given daily subcutaneous injections of either saline (control) or 30 mg/kg per day of F2MBP, dichloromethylene bisphosphonate (Cl2MBP), or 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) for 30 days. Microradiographs of the epiphysealmetaphyseal region of tibiae from animals treated with either F2MBP or Cl2MBP demonstrated increased radiodensity but, unlike those treated with HEBP, without an increase in the width of the epiphyseal growth plate. Quantitative analyses of these microradiographs showed that there was an increase of calcified tissue in the metaphyseal region in all diphosphonate groups when compared with controls. However, the HEBP-treated animals exhibited significantly less increase than either F2MBP-treated or Cl2MBP-treated rats. In addition, the total area of calcified tissue in the diaphyseal transverse sections was greater in the F2MBP-treated animals than in controls. Elemental calcium, phosphorus, and fluorine, as detected by the electron probe, also increased in the metaphyseal region of the F2MBP-treated animals, but no significant differences in the calcium: phosphorous ratio were found among the control, F2MBP, and Cl2MBP treatment groups, indicating no alterations in the chemical composition of bone. The greater amount of fluorine in the tibiae of F2MBP-treated animals reflected the presence of the F2MBP molecule. Thus, this study has demonstrated that this new fluorinated bisphosphonate, like Cl2MBP, inhibits physiologic bone remodeling without disturbing mineralization. Furthermore, the presence of fluorine in F2MBP allows the precise localization of the incorporation of the bisphosphonate within the bone.